Nausea and vomiting are commonly experienced by cancer patients in the course of their disease and treatment. Nausea and/or vomiting may be a result of the cancer itself or from its treatment. Aprepitant, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine, shown below, is a substance P/neurokinin 1 (NK1) receptor antagonist used to prevent of acute and delayed nausea and vomiting associated with moderately- and highly-emetogenic chemotherapy and to prevent postoperative nausea and vomiting (PONV).
The neuropeptide receptors for substance P (neurokinin-1: NK-1) are distributed throughout the mammalian nervous system, the circulatory system and peripheral tissues and are involved in the regulation of a number of biological processes including sensory perception of olefaction, vision, pain, vasodilation, gastric motility and movement control. Substance P antagonists are being studied for their usefulness against neuropsychiatric diseases, inflammatory diseases, pain (including migraine), skin diseases, asthma and other respiratory diseases and emesis. Substance P is known to be a major mediator of pruritus, also commonly known as itch. Studies have reported that aprepitant, as a substance P antagonist, can have a therapeutic effect in the treatment of pruritus (S. Ständer. “Targeting the neurokinin Receptor 1 with aprepitant: a novel antipruritic strategy” PLoS One. 2010; 5(6) e10968). The types of itch or skin irritation, include, but are not limited to: a) psoriatic pruritis, itch due to hemodyalisis, aguagenic pruritus, and itching caused by skin disorders (e.g., contact dermatitis), systemic disorders, neuropathy, psychogenic factors or a mixture thereof; b) itch caused by allergic reactions, insect bites, hypersensitivity (e.g., dry skin, acne, eczema, psoriasis), inflammatory conditions or injury; c) itch associated with vulvar vestibulitis; and d) skin irritation or inflammatory effect from administration of another therapeutic such as, for example, antibiotics, antivirals and antihistamines.
It has been demonstrated that NK1 receptors are overexpressed in a wide range of tumor cells and that NK1 receptor antagonists, such as aprepitant, on binding to these receptors can inhibit tumor cell proliferation, angiogenesis and migration of tumor cells. In vitro studies have shown the effectiveness of aprepitant in a range of cancer cell lines including malignant melanoma, neuroblastoma, pancreas, gastric and colon carcinoma cell lines. These studies suggest aprepitant's potential as a broad spectrum anti-tumor drug (M. Muñoz. “The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug” Invest New Drugs. 2010 April; 28(2): 187-93).
Substance P has been implicated in the response to stress, as well as reward related behaviours (P. W. Mantyh. Brain Research. 1987; 307: 147-165). Clinical trials are currently ongoing to investigate whether aprepitant, as a substance P antagonist, could have a positive effect on the cravings and dependency associated with addictive substances such as alcohol, cocaine, opioids, cannabis and tobacco.
Aprepitant is classified by the Biopharmaceutical Classification System (BCS) as a Class IV drug, indicating that it is a low solubility and low permeability API. APIs with poor water solubility are usually characterised by low absorption and poor bioavailability. Aprepitant is a white to off-white crystalline solid which is sparingly soluble in ethanol and isopropyl acetate, slightly soluble in acetonitrile but practically insoluble in water. Aprepitant is identified by CAS Registry Number: 170729-80-3. Aprepitant is disclosed in PCT application WO 95/16679 along with a process for its preparation. See also U.S. Pat. Nos. 5,719,147; 6,048,859; and 6,235,735. U.S. Pat. No. 6,096,742 describes polymorphic forms of aprepitant.
Aprepitant is currently approved for the prevention of nausea and vomiting associated with chemotherapy and also for the prevention of postoperative nausea and vomiting. It is marketed by Merck & Co., Inc, as capsules containing 40 mg, 80 mg and 125 mg of aprepitant for oral administration. Aprepitant was developed and is currently marketed as a nanoparticle formulation to overcome its poor solubility/permeability characteristics. See, e.g., U.S. Pat. No. 5,145,684. But, even with a nanoparticulate formulation, the mean absolute bioavailability of aprepitant is still only 60-65%.
There is a need therefore to develop new forms of aprepitant that have improved dissolution, solubility and/or increased bioavailability. The aprepitant compositions and cocrystals of this invention answer such needs.
PCT application PCT/IB2011/054210, published as WO 028937 A1, describes a 1:1:1 aprepitant L-proline H2O composition and cocrystal. The disclosure of this patent application is incorporated herein by reference.
Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable API. Recently, crystalline forms of API's have been used to alter the physicochemical properties of a particular API. Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a novel solid form of an API (such as a cocrystal or polymorph of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility and dissolution rates (important factors in determining bioavailability). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.
Obtaining crystalline forms of an API is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. It is also possible to achieve desired properties of a particular API by forming a cocrystai of the API and a coformer Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the cocrystal of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a cocrystal may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising a cocrystal of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
Another potentially important solid state property of an API is its dissolution rate in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
A cocrystal of an API is a distinct chemical composition of the API and coformer(s) and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer(s) individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques, Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).